title: Specific effect of immunomodulatory quinoline-3-carboxamide ABR-215757 in GM-CSF stimulated bone marrow cell cultures: block of initiation of proliferation of Gr-1+ cells.
abstract: Quinoline-3-carboxamides are currently in clinical development for treatment of both autoimmune disease and cancer. Carboxamides such as ABR-215757 (5757) have shown efficacy in several in vivo mouse models of human inflammatory autoimmune disease. Some microbial infections in mice cause GM-CSF dependent accumulation of dendritic cells expressing TNFα and inducible nitric oxide synthase (iNOS; Tip-DCs) in lymphoid organs. Functionally similar DCs develop in GM-CSF stimulated bone marrow (BM) cell cultures and offered an in vitro model that allowed us to study the impact of 5757 on cellular development of relevance for in vivo inflammatory conditions. We show in here that addition of 5757 to such cultures, in a dose-dependent way increased the frequency of DCs, while it reduced the frequency of Gr-1(+) cells by inhibiting their proliferation. This effect was specific as the compound neither influenced DC development from myeloid progenitors, nor the development of granulocytes in G-CSF stimulated BM cell cultures. Importantly, we also show that 5757 treatment reduced the accumulation of Gr-1(+) cells during inflammation in vivo. We therefore propose that this compound may ameliorate autoimmune disease by blocking proliferation of Gr-1(+) cells during inflammation-induced mobilization of myeloid cells.
authors.affiliation: Immunology group, Department of Experimental Medical Research, BMC D14, Lund University, SE-22184, Lund, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Helmersson
authors.forename: Martin
authors.initials: M
authors.lastname: Stenström
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ivars
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D040501:Calgranulin A / Q000235:genetics; D040502:Calgranulin B / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; C503133:Gr-1 protein, mouse; D007155:Immunologic Factors; C497710:N-ethyl-N-phenyl-1,2-dihydro-5-ethyl-4-hydroxy-1-methyl-2-oxoquinoline-3-carboxamide; D011804:Quinolines; D015363:Quinolones; D019707:Receptors, Chemokine; C086145:S100a8 protein, mouse; C541322:quinoline-3-carboxamide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor